1-arylethyl-3-substituted piperidines

ABSTRACT

A series of novel 1-(phenethyl) and 1-(1-heteroarylethyl)-3-substituted piperidine derivatives have been prepared, including their pharmaceutically acceptable salts and various novel key intermediates therefor. The 3-substituent present in these compounds is an unsubstituted or substituted diphenylmethoxy group or a diphenylmethoxy-derived group, while the 1-substituent is unsubstituted or substituted phenethyl or 1-(2-heteroarylethyl) wherein the heteroaryl moiety is thienyl, pyridyl or pyrazinyl. These compounds in the form of both their racemates and 3R-isomers, are useful in therapy as smooth muscle muscarinic receptor antagonists and therefore, are of value in the treatment diseases associated with altered motility and/or smooth muscle tone. The most preferred compound is (3R)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine. Methods for preparing these compounds from known starting materials are provided.

BACKGROUND OF THE INVENTION

This invention relates to certain 1,3-disubstituted piperidinederivatives.

More specifically, this invention relates to 1-arylethyl-3-substitutedpiperidine derivatives as selective muscarinic receptor antagonists.

GB-780,027 discloses, amongst other compounds, 3-(benzhydryloxy)- and3-(xanthyloxy)-N-aralkylpiperidines as oxytocic agents, being devoid ofantispasmodic activity at the therapeutic doses employed. No N-phenethylsubstituted examples were synthesised or exemplified within the scope.

U.S. Pat. No. 2,974,146 provides N-aralkyl-3-piperidyl benzhydryl ethershaving activity as sedatives and in prolonging the hypnotic effect ofbarbiturates, with only the corresponding quaternary ammonium saltsbeing stated to possess gastro-intestinal antispasmodic activity.Although N-phenethyl-3-piperidyl benzhydryl ether is listed as "aspecific compound provided by the invention", no preparative details orpharmacological data are presented and it is clear that the compound wasnever actually made.

SUMMARY OF THE INVENTION

It has now unexpectedly been discovered that the 1-(phenethyl) and1-(2-heteroarylethyl)-3-substituted piperidine derivatives provided bythe present invention are muscarinic receptor antagonists which areselective for smooth muscle muscarinic sites over cardiac muscarinicsites and which do not have any significant antihistaminic activity.Thus the compounds are useful in the treatment of diseases associatedwith altered motility and/or tone of smooth muscle which can, forexample, be found in the gut, trachea and bladder. Such diseases includeirritable bowel syndrome, diverticular disease, urinary incontinence,oesophageal achalasia and chronic obstructive airways disease.

According to the invention there are provided the 3R,S-(racemic) and3R-(optically active) forms of the compounds of the formula: ##STR1##and their pharmaceutically acceptable salts, wherein R¹ is a group ofthe formula: ##STR2## where each Y, which may be the same or different,is selected from the substituents hydrogen, halo and C₁ -C₄ alkyl; tX is--(CH₂)₂ --, --CH═CH--, --CH₂ --S--, --CH₂ --O--, --S-- or --O--; and Ris a group of the formula: ##STR3## where either R² and R³ are eachindependently hydrogen, C₁ -C₄ alkyl, hydroxy-(C₁ -C₄ alkyl), hydroxy,C₁ -C₄ alkoxy, halo, trifluoromethyl, nitro, cyano, sulphamoyl, --CO(C₁-C₄ alkyl), --OCO(C₁ -C₄ alkyl), --CO₂ (C₁ -C₄ alkyl), --(CH₂)_(n) CONR⁶R⁷, --(CH₂)_(n) OCONR⁶ R⁷, --(CH₂)_(n) NR⁸ R⁹ or --NHSO₂ NH₂ in which R⁶and R⁷ are each independently H or C₁ -C₄ alkyl, n is 0, 1 or 2, andeither R⁸ and R⁹ are each independently H or C₁ -C₄ alkyl or R⁸ ishydrogen and R⁹ is --SO₂ (C₁ -C₄ alkyl), --CO(C₁ -C₄ alkyl) or --CONH(C₁-C₄ alkyl);

or

R² and R³ taken together, and when attached to adjacent carbon atoms,represent a group of the formula --O(CH₂)_(m) O-- where m is 1, 2 or 3,--O(CH₂)₂ -- or --(CH₂)₃ --;

R⁴ is H, C₁ -C₄ alkyl or --CONH₂ ;

and

R⁵ is H, C₁ -C₄ alkyl or C₁ -C₄ alkoxy.

"Halo" means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or 4 carbonatoms can be straight or branched chain. The preferred alkyl and alkoxygroups are methyl, ethyl, methoxy and ethoxy.

Preferred groups for R¹ include: ##STR4##

In one aspect, each Y is preferably the same.

When R is an optionally substituted phenyl group, then it preferably hasthe formula: ##STR5## where R² and R³ are as defined for formula (I).

When R is an optionally substituted thiophene group, it preferably hasthe formula: ##STR6## where R⁴ is as defined for formula (I).

Preferred groups for R include the following: ##STR7## where either R²and R³ are each independently hydrogen, C₁ -C₂ alkyl, hydroxy-(C₁ -C₃alkyl), hydroxy, C₁ -C₂ alkoxy, halo, sulphamoyl, --CO(C₁ -C₂ alkyl),--OCO(C₁ -C₂ alkyl), --CONH₂, --CONH(C₁ -C₂ alkyl), --OCONH(C₁ -C₂alkyl), --NH₂, --CH₂ NH₂, --CH₂ NH(C₁ -C₂ alkyl), --NHSO₂ (C₁ -C₂alkyl), --NHCO(C₁ -C₂ alkyl), --CH₂ NHCO(C₁ -C₂ alkyl), --CH₂ NHCONH(C₁-C₂ alkyl) or --NHSO₂ NH₂ ; or R² and R³ taken together represent--O(CH₂)_(m) O-- where m is 1, 2 or 3, --O(CH₂)₂ --, or --(CH₂)₃ --;##STR8##

R¹ is most preferably: ##STR9##

R is most preferably: ##STR10##

The compounds of the formula (I) contain at least one asymmetric centreand will therefore exist as a pair of enantiomers or as diastereomericpairs of enantiomers. Such enantiomers or diastereomeric pairs ofenantiomers may be resolved by physical methods, e.g. by fractionalrecrystallisation, chromatography or H.P.L.C. of a racemic mixture ofthe compound of the formula (I), or of a suitable salt or derivativethereof. Most preferably, the individual enantiomers of the compounds ofthe formula (I) containing one asymmetric centre are prepared fromoptically pure intermediates.

The anticholinergic activity of the present compounds resides primarilyin the 3R-forms, i.e., the compounds having R stereochemistry atposition 3 of the piperidine ring, hence the invention is restricted tothe 3R- and 3R,S-(racemic) forms of the compounds (I).

A particularly preferred individual compound of the invention is(3R)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine of apharmaceutically acceptable salt thereof.

The invention also includes certain synthetic intermediates, namely the3R,S- and 3R-forms of the compounds of the following formulae: ##STR11##R and R¹ being as defined for formula (I).

The pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts such as the hydrochloride, hydrobromide,sulphate or bisulphate, phosphate or hydrogen phosphate, acetate,besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate,succinate and tartrate salts. For a more comprehensive list ofpharmaceutically acceptable salts see, for example, the Journal ofPharmaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. Thesesalts can be prepared conventionally, e.g. by mixing a solution of thefree base and the acid in a suitable solvent, e.g. ethanol, andrecovering the acid addition salt either as a precipitate, or byevaporation of the solution.

The compounds of the formula (I) can be prepared by a number of routes,including the following:

DETAILED DESCRIPTION OF THE INVENTION Route A

This can be illustrated as follows: ##STR12##

R and R¹ are as defined for formula (I) and Q is a leaving group, e.g.Br, Cl, I, C₁ -C₄ alkanesulfonyloxy (e.g. methanesulfonyloxy),benzenesulfonyloxy, toluenesulfonyloxy (e.g. p-toluenesulfonyloxy) ortrifluoromethanesulfonyloxy. Preferably, Q is Cl, Br, I ormethanesulfonyloxy.

The reaction is preferably carried out in the presence of an acidacceptor such as sodium or potassium carbonate, sodium bicarbonate,triethylamine or pyridine, and in a suitable organic solvent, e.g.acetonitrile, at up to the reflux temperature. Reaction temperatures of60°-120° C. are generally desirable and it is most convenient to carryout the reaction under reflux. Iodo is generally the most suitableleaving group but since the starting materials (III) are generally mostconveniently available as chlorides or bromides, the reaction is oftenmost suitably carried out using the compound (III) as a chloride orbromide but in the presence of an iodide such as sodium or potassiumiodide. In the preferred technique, the compounds (II) and (III), (III)being in bromide or chloride form, are refluxed together in acetonitrilein the presence of sodium carbonate and sodium iodide. The product (I)can be isolated and purified conventionally.

The 3R,S- or 3R-forms of the starting material (II) should be usedaccording to whether the 3R,S- or 3R-products are desired.

The starting materials of the formula (II) can be obtained byconventional procedures such as those described in Preparations 1 to 7.The starting materials of the formula (III) are in general knowncompounds which can be prepared by conventional techniques. Thepreparation of the novel starting materials of the formula (III) used inthe Examples is described in the following Preparations section.

Route B

This route can be illustrated as follows: ##STR13##

R and R¹ are as defined for formula (I): again the 3R,S- or 3R-form ofthe compound (IV) should be used as appropriate.

The reduction can be carried out conventionally, typically by using aninorganic reducing agent such as lithium aluminium hydride, aluminiumhydride (AlH₃ --made in situ from lithium aluminium hydride andconcentrated sulfuric acid) or diborane in a suitable organic solventsuch as tetrahydrofuran, ether or dioxane. The reaction is preferablycarried out at from 0° C. to room temperature. Heating is generally notneeded although, if required, the reaction can be carried out at up tothe reflux temperature of the reaction mixture. Again the product (I)can be isolated and purified conventionally.

The starting materials (3R,S- or 3R-) of the formula (IV) can beprepared by conventional techniques including those which are describedin the following Preparations (see particularly Preparations 8 to 14).

Route C

This route can be illustrated as follows: ##STR14##

R and R¹ are as defined for formula (I) and Q is a leaving group such asdescribed in Route A. In this route, Q is preferably Cl or Br. Where thecompound (V) is fairly reactive, then the reaction will proceed tocompletion at room temperature. If necessary, the reaction mixture canbe heated at up to, say, 160° C., to accelerate the rate of reaction.The reaction can be carried in a suitable organic solvent, e.g.methylene chloride, although in some instances, as in Example 8(B), thepresence of a separate organic solvent is unnecessary. The compound (I)can be isolated and purified conventionally.

The starting materials (V) are either known compounds or can be preparedconventionally. The compounds (VI) can be prepared conventionally, e.g.by the techniques described in Preparations 15 and 16. Again the 3R,S-or 3R-form of the starting material (VI) should be used according towhether the 3R,S- or 3R-form of the compound (I) is desired.

Route D

This route is useful for preparing compounds in which R is 2-or4-pyridyl or pyrazinyl and can be described as follows: ##STR15##

R¹ and R⁵ are as defined for formula (I). Clearly the vinyl group mustbe attached to the 2- or 4-position of the pyridine ring.

The reaction is typically carried out with heating at up to 160° C.,preferably 80° to 140° C., in a suitable organic solvent, e.g.1-butanol. The use of a basic (preferably a strong base which is solublein an organic solvent such as N-benzyltrimethylammonium hydroxide["Triton B"--Trade Mark]) or acidic (preferably a C₁ -C₄ alkanoic acid)catalyst is useful. The preferred procedure is to reflux the reactantsin the organic solvent in the presence of a basic catalyst such as"Triton B".

Route E

Compounds in which R is 5-carbamoyl-2-thienyl can also be made by thefollowing route: ##STR16##

R¹ is as defined for formula (I).

Some of the compounds of the formula (I) in which R is a substitutedphenyl group can be converted to other compounds of the formula (I) asfollows:

(a) A --CO₂ (C₁ -C₄ alkyl) substituent on the phenyl group can bereduced to --CH₂ OH. Lithium aluminium hydride is the most suitablereducing agent. The reaction is typically carried in a suitable organicsolvent, e.g. ether, at between 0° and room temperature. It is generallymost convenient to use the starting material in the form of its methylester.

(b) A hydroxy substituent on the phenyl group can be converted to--OCO(C₁ -C₄ alkyl) by acylation using a C₁ -C₄ alkanoyl chloride orbromide or a C₁ -C₄ alkanoic anhydride. The presence of an acid acceptoris preferable. The reaction is typically carried out at about roomtemperature in a suitable organic solvent, e.g. dioxan.

(c) A --CO(C₁ -C₃ alkyl) substituent on the phenyl group can be reducedto a substituent of the formula --CH(OH)(C₁ -C₃ alkyl). Suitablereducing agents include sodium borohydride and lithium aluminiumhydride. The reaction is typically carried out at between 0° and roomtemperature in a suitable organic solvent, e.g. methanol. Sodiumborohydride is the preferred reducing agent.

(d) A --CO₂ (C₁ -C₄ alkyl) substituent, preferably --CO₂ CH₃, can beconverted to --CONR⁶ R⁷ by reaction with ammonia or the appropriateamine R⁶ R⁷ NH. When R⁶ and R⁷ are both H, the use of aqueous (0.880)ammonia is generally most convenient, although the reaction can becarried out using ammonia in an organic solvent such as methanol orethanol, or ammonia neat in a bomb. The reaction with methylamine ismost conveniently carried out in ethanol. Although in some instances thereaction may proceed at a satisfactory rate at room temperature, heatingat up to 120°, preferably 60° to 100° C., is generally necessary. Forvolatile amines, the reaction is best carried out in a bomb.

(e) A nitro substituent on the phenyl group can be reduced to amino byconventional means. The preferred reducing agent is stannous chloridedihydrate and the reaction is typically carried out in an organicsolvent such as ethanol under reflux.

(f) An amino substituent on the phenyl group can be converted to --NHSO₂(C₁ -C₄ alkyl) by reaction with a C₁ -C₄ alkanesulphonyl chloride orbromide or C₁ -C₄ alkanesulphonic anhydride. The presence of an acidacceptor such as pyridine, triethylamine, sodium bicarbonate or sodiumor potassium carbonate, is preferable. It is often most convenient,particularly when a sulphonyl chloride is used, to carry out thereaction in pyridine, the pyridine functioning as both the solvent andthe acid acceptor. Heating is not usually necessary: normally thereaction will proceed at a satisfactory rate at room temperature.

(g) A substituent of the formula --(CH₂)_(n) NH₂ where n is 0, 1 or 2can be converted to --(CH₂)_(n) NHCO(C₁ -C₄ alkyl) by reaction with a C₁-C₄ alkanoyl chloride or bromide or C₁ -C₄ alkanoic anhydride. Thereaction can be carried out similarly to (f) above. The use of aceticanhydride in ethyl acetate/water with sodium bicarbonate as the acidacceptor is a preferred reaction.

(h) An amino substituent on the phenyl group can also be converted tosulphamoyl by reaction with sulphamide, typically under reflux in anorganic solvent such as dioxan.

(i) A hydroxy substituent can be converted to C₁ -C₄ alkoxy firstly byreaction with a strong base such as sodium hydride, and then by reactionwith a C₁ -C₄ alkyl iodide. The reaction is preferably carried out atabout room temperature in a solvent such as dimethylformamide.

(j) A hydroxy substituent of the formula --(CH₂)_(n) OH where n is 0, 1or 2 can be converted to --(CH₂)_(n) OCONH(C₁ -C₄ alkyl) by reactionwith a C₁ -C₄ alkyl isocyanate. The reaction is typically carried out atabout room temperature in a solvent such as methylene chloride.

(k) A hydroxymethyl substituent on the phenyl group can be converted to--CH₂ NR⁸ R⁹ where R⁸ and R⁹ are each independently H or C₁ -C₄ alkyl byreaction firstly with thionyl chloride and secondly with ammonia or theappropriate amine R⁸ R⁹ NH. The reaction with thionyl chloride istypically carried out with heating, preferably under reflux, in asolvent such as methylene chloride. The reaction with ammonia or theamine is typically carried out at about room temperature in a solventsuch as ethanol.

(1) An acetyl substituent can be converted to --C(OH)(CH₃)₂ by reactionwith methyllithium, methylmagnesium bromide, methylmagnesium iodide ormethylmagnesium chloride. The reaction is typically carried out in asolvent such as ether at a temperature of from 0° C. to roomtemperature.

(m) An iodo substituent can be converted to C₁ -C₄ alkoxycarbonyl byreaction, typically at about room temperature, with carbon monoxide in aC₁ -C₄ alkanol containing a base [e.g. potassium carbonate] and apalladium (II) catalyst [e.g. bis(triphenylphosphine)palladium (II)chloride].

(n) A cyano substituent on the phenyl group can be reduced toaminomethyl, typically by catalytic hydrogenation, e.g. using H₂ /Pd/Cin ethanol containing a small amount of concentrated hydrochloric acid.

(o) A substituent of the formula --(CH₂)_(n) NH₂ where n is 0, 1 or 2can be converted to a substituent of the formula --(CH₂)_(n) NHCONH(C₁-C₄ alkyl) by reaction with a C₁ -C₄ alkyl isocyanate. The reaction istypically carried out at about room temperature in a solvent such asmethylene chloride. And

(p) A C₁ -C₄ alkoxy substituent, preferably methoxy, can be converted tohydroxy by treatment with a C₁ -C₄ alkanethiol in the presence of astrong base, e.g. sodium hydride. The reaction is typically carried outby refluxing the reactants in a suitable solvent, e.g.dimethylformamide. Butanethiol is the preferred thiol.

The selectivity of the compounds as muscarinic receptor antagonists canbe measured as follows.

Male guinea pigs are sacrificed and the ileum, trachea, bladder andright atrium are removed and suspended in physiological salt solutionunder a resting tension of 1 g at 32° C. aerated with 95% O₂ and 5% CO₂.contractions of the ileum, bladder and trachea are recorded using anisotonic (ileum) or isometric transducer (bladder and trachea). Thefrequency of contraction of the spontaneously beating right atrium isderived from isometrically recorded contractions.

Dose-response curves to either acetylcholine (ileum) or carbachol(trachea, bladder and right atrium) are determined using a 1-5 minutecontact time for each dose of agonist until the maximum response isachieved. The organ bath is drained and refilled with physiological saltsolution containing the lowest dose of the test compound. The testcompound is allowed to equilibrate with the tissue for 20 minutes andthe agonist dose-response curve is repeated until the maximum responseis obtained. The organ bath is drained and refilled with physiologicalsalt solution containing the second concentration of test compound andthe above procedure is repeated. Typically four concentrations of thetest compound are evaluated on each tissue.

The concentration of the test compound which causes a doubling of theagonist concentration to produce the original response is determined(pA₂ value--Arunlakshana and Schild (1959, Brit. J. Pharmacol., 14,48-58). Using the above analytical techniques, tissue selectivity formuscarinic receptor antagonists is determined.

Activity against agonist induced bronchoconstriction, gut or bladdercontractility in comparison with changes in heart rate is determined inthe anaesthetised dog. Oral activity is assessed in the conscious dogdetermining compound effects on, for example, heart rate, pupil diameterand gut motility.

Compound affinity for other cholinergic sites is assessed in the mouseafter either intraveous or intraperitoneal administration. Thus, thedose to cause a doubling of pupil size is determined as well as the doseto inhibit by 50% the salivation and tremor responses to intravenousoxotremorine.

For administration to man in the curative or prophylactic treatment ofdiseases associated with the altered motility and/or tone of smoothmuscle, such as irritable bowel syndrome, diverticular disease, urinaryincontinence, oesophageal achalasia and chronic obstructive airwaysdisease, oral dosages of the compounds will generally be in the range offrom 3.5 to 350 mg daily for an average adult patient (70 kg). Thus fora typical adult patient, individual tablets or capsules will typicallycontain from 1 to 250 mg of active compound, in a suitablepharmaceutically acceptable vehicle or carrier for administration singlyor in multiple doses, once or several times a day. Dosages forintravenous administration will typically be within the range 0.35 to 35mg per single dose as required. In practice the physician will determinethe actual dosage which will be most suitable for an individual patientand it will vary with the age, weight and response of the particularpatient. The above dosages are exemplary of the average case but therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

For human use, the compounds of the formula (I) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theymay be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs orsuspensions containing flavouring or colouring agents. They may beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

In a further aspect the invention provides a pharmaceutical compositioncomprising a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.

The invention also includes a compound of the formula (I) or apharmaceutically acceptable salt thereof, for use as a medicament,particularly for use in the treatment of irritable bowel syndrome.

The invention further includes the use of a compound of the formula (I),or of a pharmaceutically acceptable salt thereof, for the manufacture ofa medicament for the treatment of diseases associated with the alteredmotility and/or tone of smooth muscle, such as irritable bowel syndrome,diverticular disease, urinary incontinence, oesophageal achalasia andchronic obstructive airways disease.

The following Examples, in which all temperatures are in °C., illustratethe invention:

EXAMPLE 1(3R,S)-Diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine MethodA ##STR17##

A solution of(3R,S)-diphenylmethoxy-1-(3,4-methylenedioxyphenylacetyl)piperidine(1.08 g) (see Preparation 8) in tetrahydrofuran (10 ml) was addeddropwise over 10 minutes to a stirred, ice-cooled suspension of lithiumaluminium hydride (0.20 g) in tetrahydrofuran (15 ml), and the mixturewas stirred at room temperature for 3 hours, quenched by the addition ofsaturated aqueous ammonium chloride solution until a white precipitateformed, and then filtered. The filtrate was evaporated and the residuepurified by chromatography on silica using methylene chloride containing0-5% methanol as the eluant. Appropriate fractions were combined andevaporated to give the desired product as a pale yellow oil (0.54 g,52%) which contained 0.25 molar equivalents of water.

Analysis %: Found: C, 77.2; H, 7.2; N, 3.3; C₂₇ H₂₉ NO₃ ; 0.25H₂ Orequires: C, 77.2; H, 7.0; N, 3.3.

Method B: ##STR18##

A mixture of (3R,S)-diphenylmethoxypiperidine (2.67 g) (see Preparation1), 3,4-methylenedioxyphenethyl bromide (2.29 g) (see Preparation 20),sodium carbonate (2.10 g) and sodium iodide (0.25 g) in acetonitrile (50ml) was heated under reflux for 68 hours, diluted with ethyl acetate andwater, and the layers were separated. The organic layer was washed withwater, dried over magnesium sulphate and evaporated. The residue waspurified by chromatography on silica (50 g) using methylene chloridecontaining 0-5% methanol as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a pale yellow oil(3.20 g, 77%), whose spectral data was identical with that of theproduct obtained by Method A.

¹ H n.m.r. (CDCl₃): δ=7.22-7.64 (10H, m); 7.61-7.80 (3H, m); 5.93 (2H,s); 5.58 (1H, s); 3.52-3.64 (1H, m); 3.13 (1H, dd, J=6 and 2 Hz);2.54-2.85 (5H, m) and 1.30-2.17 (6H, m).

EXAMPLES 2-7

The following compounds (R,S-forms) were prepared by reduction of theappropriate (3R,S)-starting materials with lithium aluminium hydride asdescribed in Example 1, Method A. All the compounds were obtained ascolourless oils and were characterised as such.

Example 2 was characterised by ¹ H-n.m.r.; (CDCl₃): δ=7.2-7.5 (10H, m);6.60-6.88 (3H, m); 5.60 (1H, s); 4.24 (4H, s); 3.52-3.65 (1H, m); 3.09(1H, d, J=6 Hz); 2.54-2.88 (5H, m) and 1.25-2.15 (6H, m). ##STR19##

The piperidine starting materials are described in Preparations 9-14.

    __________________________________________________________________________                                Analysis %                                                                    (Theoretical in brackets)                         Example                                                                            R            Form Characterised                                                                      C   H   N                                         __________________________________________________________________________          ##STR20##   Free base Characterised by .sup.1 H-n.m.r. (vide                                        infra)                                            3                                                                                   ##STR21##   Free base 73.4 (73.8                                                                        6.4 6.4                                                                           3.1 3.2)                                  4                                                                                   ##STR22##   Free base 81.3 (81.0                                                                        7.6 7.5                                                                           3.4 3.4)                                  5                                                                                   ##STR23##   Free base, 0.25 H.sub.2 O                                                               75.4 (75.8                                                                        6.7 6.7                                                                           3.7 3.4)                                  6                                                                                   ##STR24##   Free base 79.8 (80.2                                                                        7.3 7.2                                                                           3.5 3.6)                                  7                                                                                   ##STR25##   Free base 78.2 (78.5                                                                        7.5 7.5                                                                           3.2 3.2)                                  __________________________________________________________________________

EXAMPLE 8 (3R,S)-Diphenylmethoxy-1-(3-methoxyphenethyl)piperidine MethodA ##STR26##

This was prepared as described in Example 1, Method B using3-methoxyphenethyl bromide instead of 3,4-methylenedioxyphenethylbromide. The title compound was obtained as a colourless oil (1.37 g,68%).

Analysis %: Found: C, 80.5; H, 7.8; N, 3.3; C₂₇ H₃₁ NO₂ requires: C,80.8; H, 7.8; N, 3.5.

Method B ##STR27##

An intimate mixture of (3R,S)-hydroxy-1-(3-methoxyphenethyl)piperidine(1.00 g) (see Preparation 16) and bromodiphenylmethane (0.95 g) washeated at 140° for one hour, allowed to cool to room temperature,dissolved in methylene chloride, washed with 10% aqueous sodiumcarbonate solution, dried over magnesium sulphate and evaporated. Theresidue was purified by chromatography on silica (10 g) using methylenechloride as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless oil (0.45 g, 27%)whose spectral data was identical with that of the material obtained byMethod A.

¹ H-n.m.r. (CDCl₃): δ=7.14-7.44 (11H, m); 6.72-6.90 (3H, m); 5.59 (1H,s); 3.80 (3H, s); 3.50-3.63 (1H, m); 3.15 (1H, dd, J=6 and 2 Hz);2.58-2.86 (5H, m) and 1.27-2.16 (8H, m).

EXAMPLES 9-25

The following compounds (R,S-forms) were prepared by reacting(3R,S)-diphenylmethoxypiperidine with the appropriate alkylating agentas described in Example 1, Method B. The alkylating agents are eitherknown compounds or are described in Preparations 24, 25 and 27. All thecompounds were obtained as colourless oils and were characterised assuch except where indicated.

Examples 17 and 23 were characterised by ¹ H-n.m.r.:

Example 17 (CDCl₃): δ=7.99 (2H, d, J=8 Hz); 7.22-7.46 (12H, m); 5.58(1H, s); 3.96 (3H, s); 3.52-3.62 (1H, m); 3.10 (1H, d, J=6 Hz);2.60-2.90 (5H, m) and 1.25-2.20 (6H, m).

Example 23 (CDCl₃): δ=6.98-7.63 (14H, m); 5.60 (1H, s); 3.52-3.64 (1H,m); 3.10 (1H, d, J=6 Hz); 2.56-2.80 (5H, m) and 1.26-2.18 (6H, m).##STR28##

    __________________________________________________________________________                              Analysis                                                               Form   (Theoretical in brackets)                           Example                                                                            R           Q Characterised                                                                        C   H   N                                           __________________________________________________________________________     9                                                                                             Cl                                                                              Free base, m.p. 108-109°                                                      63.3 (62.8                                                                        5.8 5.7                                                                           2.7 2.8)                                    10                                                                                  ##STR29##  Cl                                                                              Free base                                                                            77.8 (77.9                                                                        7.8 7.7                                                                           3.5 3.2)                                    11                                                                                  ##STR30##  Cl                                                                              Free base                                                                            72.6 (72.6                                                                        6.8 6.8                                                                           6.5 6.3)                                    12                                                                                  ##STR31##  Br                                                                              Free base                                                                            75.4 (75.0                                                                        6.9 6.8                                                                           6.8 6.7)                                    13                                                                                  ##STR32##  Br                                                                              Free base                                                                            74.6 (75.0                                                                        6.6 6.8                                                                           7.0 6.7)                                    14                                                                                  ##STR33##  Br                                                                              Free base                                                                            80.4 (80.2                                                                        7.2 7.2                                                                           3.7 3.6)                                    15                                                                                  ##STR34##  Br                                                                              Free base, 0.25 H.sub.2 O                                                            79.7 (79.7                                                                        7.6 7.6                                                                           3.6 3.6)                                    16                                                                                  ##STR35##  Br                                                                              Free base                                                                            83.6 (84.0                                                                        7.5 7.9                                                                           4.2 3.8)                                    17                                                                                  ##STR36##  Br                                                                              Free base                                                                            Characterised by .sup.1 H-n.m.r. (vide infra)       18                                                                                  ##STR37##  Br                                                                              Free base                                                                            81.2 (81.3                                                                        7.6 7.6                                                                           3.2 3.4)                                    19                                                                                  ##STR38##  Cl                                                                              Free base, m.p. 114-115°                                                      72.0 (72.2                                                                        6.6 6.5                                                                           6.4 6.5)                                    20                                                                                  ##STR39##  Br                                                                              Free base, m.p. 138-140°                                                      80.1 (80.6                                                                        7.4 7.5                                                                           3.6 3.6)                                    21                                                                                  ##STR40##  Br                                                                              Free base                                                                            75.9 (76.3                                                                        7.3 7.2                                                                           4.1 3.7)                                    22                                                                                  ##STR41##  Br                                                                              Free base                                                                            80.6 (80.8                                                                        7.8 7.8                                                                           3.4 3.5)                                    23                                                                                  ##STR42##  Br                                                                              Free base                                                                            Characterised by .sup.1 H-n.m.r. (vide infra)       24                                                                                  ##STR43##  Br                                                                              Free base                                                                            74.9 (75.0                                                                        6.7 6.8                                                                           6.6 6.7)                                    25                                                                                  ##STR44##  Cl                                                                              Free base                                                                            80.7 (80.8                                                                        7.8 7.8                                                                           3.5 3.5)                                    __________________________________________________________________________

EXAMPLE 26(3R,S)-Di(4-fluorophenyl)methoxy-1-(3,4-methylenedioxyphenethyl)piperidine##STR45##

This was prepared as described in Example 1, Method B using(3R,S)-di(4-flourophenyl)methoxypiperidine (see Preparation 2) insteadof (3R,S)-diphenylmethoxypiperidine. The title compound was obtained asa colourless oil (0.70 g, 78%).

Analysis %: Found: C, 72.4; H, 6.2; N, 3.0; C₂₇ H₂₇ F₂ NO₃ requires: C,71.8; H, 6.0; N, 3.1.

EXAMPLE 271-[2-(Benzodioxan-6-yl)ethyl]-(3R,S)-di(4-fluorophenyl)methoxypiperidine##STR46##

This was prepared by reacting (3R,S)-di(4-fluorophenyl)methoxypiperidine(see Preparation 2) and 6-(2-bromoethyl)benzodioxan (see Preparation 23)according to the procedure described in Example 1, Method B. The titlecompound was obtained as a colourless oil which was characterised as ahydrate (0.44 g, 51%).

Analysis %: Found: C, 70.0; H, 6.3; N, 2.8; C₂₈ H₂₉ F₂ NO₃.H₂ Orequires: C, 69.6; H, 6.4; N, 2.9.

EXAMPLE 28(3R)-Di(4-fluorophenyl)methoxy-1-(3-methoxyphenethyl)piperidine##STR47##

This was prepared by the procedure described in Example 1, Method B from(3R)-di(4-fluorophenyl)methoxypiperidine (see Preparation 3) and3-methoxyphenethyl bromide. The title compound was obtained as acolourless oil, (0.33 g, 38%).

Analysis %: Found: C, 73.9; H, 6.6; N, 3.1; C₂₇ H₂₉ F₂ NO₂ requires: C,74.1; H, 6.6; N, 3.2.

EXAMPLE 29(3R)-[(R,S)-1-(2-methylphenyl)-1-phenylmethoxy]-1-(4-methylphenethyl)piperidine##STR48##

This was prepared by the procedure described in Example 1, Method B from(3R)-[(R,S)-1-(2-methylphenyl)-1-phenylmethoxy]piperidine (seePreparation 4) and 4-methylphenethyl bromide. The title compound wasobtained as a pale yellow oil, (0.51 g, 70%), [α]_(D) ¹⁴ +19.7° (c 1.16in methanol).

Analysis %: Found: C, 84.1; H, 8.6; N, 3.5; C₂₈ H₃₃ NO requires: C,84.2; H, 8.3; N, 3.5.

EXAMPLE 30(3R)-[1-(2-tert-butylphenyl)-1-phenylmethoxy]-1-(4-methoxyphenethyl)piperidine;Diastereomers A and B ##STR49##

A mixture of(3R)-[(R,S)-1-(2-tert-butylphenyl)-1-phenylmethoxy]piperidine (seePreparation 5) (420 mg), 4-methoxyphenethyl bromide (288 mg), potassiumiodide (108 mg) and sodium hydrogen carbonate (169 mg) in acetonitrile(50 ml) was heated under reflux for 16 hours, filtered and evaporated.The residue was purified by chromatography on silica (10 g) usingdichloromethane plus 0-4% methanol as eluant. The initialproduct-containing fractions were combined and evaporated to give thetitle compound, diastereomer A, as a colourless solid, (300 mg, 50%),m.p. 117° C.

Analysis %: Found: C, 81.3; H, 8.9; N, 2.9; C₃₁ H₃₉ NO₂ requires: C,81.4; H, 8.6; N, 3.1.

Further elution provided, after combination and evaporation ofappropriate fractions, the title compound, diastereomer B, as acolourless solid, (253 mg, 43%), m.p. 108°-113° C.

Analysis %: Found: C, 79.8; H, 8.9; N, 2.7; C₃₁ H₃₉ NO₂.0.5H₂ Orequires: C, 79.8; H, 8.6; N, 3.0.

EXAMPLE 31(3R,S)-[(11H)-6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy]-1-(3-methoxyphenethyl)]piperidine##STR50##

The title compound was prepared by reacting(3R,S)-[(11H)-6,11-dihydrodibenzo[b,e]thiepin-11-yloxy]piperidine (seePreparation 6) and 3-methoxyphenethyl bromide according to the proceduredescribed in Example 1, Method B. The title compound was obtained as acolourless oil (0.12 g, 11%).

Analysis %: Found: C, 75.4; H, 6.8; N, 2.8; C₂₈ H₃₁ NO₂ S requires: C,75.5; H, 7.0; N, 3.1.

EXAMPLE 32(3R)-Diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine ##STR51##

This was prepared as described in Example 1, Method B using(3R)-diphenylmethoxypiperidine {[α]_(D) ²⁵ -3.3° (c 1.5 in ethanol)}(see Preparation 7) instead of (3R,s)-diphenylmethoxypiperidine. Thetitle compound was obtained as a colourless solid afterrecrystallisation from hexane (1.25 g, 78%), m.p. 52°-55° C., [α]²⁵+22.5° (c 1.5 in ethanol).

Analysis %: Found: C, 78.4; H, 7.2; N, 3.3; C₂₇ H₂₉ NO₃ requires: C,78.0; H, 7.0; N, 3.4.

EXAMPLES 33-52

The following compounds (R-forms) were prepared by reacting(3R)-diphenylmethoxypiperidine (see Preparation 7) [α]_(D) ²⁵ -3.0° (c1.5 in ethanol) with the appropriate alkylating agent as described inExample 1, Method B. The alkylating agents are either known compounds orare described in Preparations 21, 23, 29 and 31. The compounds werecharacterised as the free bases in the forms indicated. ##STR52##

    __________________________________________________________________________                                               Analysis %                                                 Form               (Theoretical in brackets)          Example                                                                            R            Q     Characterised                                                                         Optical Rotation                                                                         C   H   N                          __________________________________________________________________________    33                                                                                              Br    oil     [α].sub.D.sup.25 + 23.9° (c                                      1.5 in ethanol)                                                                           78.1 (78.3                                                                       7.4 7.3                                                                           3.0 3.3)                   34                                                                                  ##STR53##   Br    oil     [α].sub.D.sup.25 + 20.7° (c                                      1.5 in ethanol)                                                                           80.1 (80.8                                                                       7.8 7.8                                                                           3.5 3.5)                   35                                                                                  ##STR54##   Br    m.p. 156-158°                                                                  [α].sub.D.sup.25 + 23.8° (c                                      1.0 in methanol)                                                                          80.2 (80.6                                                                       7.5 7.5                                                                           3.4 3.6)                   36                                                                                  ##STR55##   Br    oil, hemihydrate                                                                      [α].sub.D.sup.25 + 25.3° (c                                      1.035 in methanol)                                                                        79.1 (79.0                                                                       7.7 7.9                                                                           3.2 3.4)                   37                                                                                  ##STR56##   OSO.sub.2 Me                                                                        oil, hemihydrate                                                                      [α].sub.D.sup.25 + 19.0° (c                                      1.005 in methanol)                                                                        68.2 (68.5                                                                       7.2 7.2                                                                           5.9 5.9)                   38                                                                                  ##STR57##   Cl    m.p. 176-178°                                                                  [α].sub.D.sup.25 + 20.2° (c                                      0.87 in methanol)                                                                         69.6 (69.3                                                                       6.7 6.7                                                                           6.2 6.2)                   39                                                                                  ##STR58##   Br    m.p. 74-76°                                                                    [α].sub.D.sup.25 + 22.2° (c                                      0.98 in methanol)                                                                         76.9 (77.4                                                                       7.3 7.2                                                                           3.3 3.5)                   40                                                                                  ##STR59##   Cl    0.25 H.sub. 2 O, oil                                                                  --          76.9 (76.8                                                                       7.6 7.5                                                                           3.2 3.3)                   41                                                                                  ##STR60##   Br    oil     --          83.8 (84.1                                                                       7.9 8.1                                                                           3.6 3.6)                   42                                                                                  ##STR61##   Cl    oil     --          81.6 (81.3                                                                       7.8 7.6                                                                           2.9 3.4)                   43                                                                                  ##STR62##   Br    oil, hemihydrate                                                                      [α].sub.D.sup.25 + 19.4° (c                                      1.025 in methanol)                                                                        80.4 (80.0                                                                       7.1 7.0                                                                           6.6 6.9)                   44                                                                                  ##STR63##   Br    m.p. 68-70°                                                                    --          77.7 (78.3                                                                       7.3 7.3                                                                           3.0 3.3)                   45                                                                                  ##STR64##   Cl    m.p. 118.5-119.5                                                                      [α].sub.D.sup.25 + 27.8° (c                                      1.07 in methanol)                                                                         77.5 (77.7                                                                       7.6 7.6                                                                           3.0  3.3)                  46                                                                                  ##STR65##   Br    oil     [α].sub.D.sup.25 + 20.4° (c                                      1.5 in ethanol)                                                                           76.8 (76.9                                                                       7.0 6.9                                                                           3.5 3.4)                   47                                                                                  ##STR66##   Br    oil     [α].sub.D.sup.25 + 24.9° (c                                      1.5 in ethanol)                                                                           84.5 (84.6                                                                       7.9 8.1                                                                           3.4 3.4)                   48                                                                                  ##STR67##   Br    oil     [α].sub.D.sup.25 + 16.7° (c                                      1.5 in ethanol)                                                                           71.3 (70.9                                                                       6.3 6.2                                                                           3.3 3.2)                   49                                                                                  ##STR68##   Br    oil, 0.25 hydrate                                                                     --          83.4 (83.1                                                                       7.7 7.9                                                                           3.8 3.7)                   50                                                                                  ##STR69##   Br    oil     --          77.6 (77.8                                                                       7.7 7.6                                                                           3.5 3.2)                   51                                                                                  ##STR70##   Br    oil     --          81.7 (81.4                                                                       7.6 7.5                                                                           3.1 3.4)                   52                                                                                  ##STR71##   Br    oil     --          64.0 (62.9                                                                       6.1 5.6                                                                           3.4 2.8)                   __________________________________________________________________________

EXAMPLE 53 1-(4-Acetoxyphenethyl)-(3R)-diphenylmethoxypiperidine##STR72##

A solution of acetyl chloride (33 ml) in dioxan (5 ml) was addeddropwise over thirty minutes to a stirred mixture of(3R)-diphenylmethoxy-1-(4-hydroxyphenethyl)piperidine (150 mg) (seeExample 35), tetrabutylammonium hydrogen sulphate (2.7 mg) (a phasetransfer catalyst) and powdered sodium hydroxide (50 mg) in dioxan (15ml) and the mixture was stirred at room temperature for four days,filtered and evaporated. The residue was purified by chromatography onsilica (5 g) using methylene chloride plus 0-5% methanol as the eluant.Appropriate fractions were combined and evaporated to give the titlecompound as a colourless oil (128 mg, 74%), [α]_(D) ²⁵ +24.4° (c 0.775in methanol).

Analysis %: Found: C, 78.3; H, 7.3; N, 3.5; C₂₈ H₃₁ NO₃ requires: C,78.3; H, 7.3; N, 3.3.

EXAMPLE 54 (3R,S)-Diphenylmethoxy-1-[2-(4-pyridyl)ethyl]piperidine##STR73##

A mixture of (3R,S)-diphenylmethoxypiperidine (534 mg) (see Preparation1), 4-vinylpyridine (630 mg) and 40% aqueous N-benzyltrimethylammoniumhydroxide ("Triton B"--Trade Mark) solution (5 drops) in 1-butanol (20ml) was heated under reflux for 70 hours and then evaporated. Theresidue was partitioned between ethyl acetate and water and the organiclayer was washed with water, dried over sodium sulphate and evaporated.The residue was purified by chromatography on silica (8 g) usingmethylene chloride plus 0-5% methanol as the eluant. Appropriatefractions were combined and evaporated to give the title compound as apale brown gum (310 mg, 42%).

Analysis %: Found: C, 80.3; H, 7.5; N, 7.8; C₂₅ H₂₈ N₂ O requires: C,80.6; H, 7.6; N, 7.5.

EXAMPLE 55 (3R,S)-Diphenylmethoxy-1-[2-(2-pyridyl)ethyl]piperidine##STR74##

This was prepared as described in Example 54 using 2-vinylpyridineinstead of 4-vinylpyridine. The title compound was obtained as a palebrown gum (240 mg, 32%).

Analysis %: Found: C, 80.9; H, 7.6; N, 7.5; C₂₅ H₂₈ N₂ O requires: C,80.6; H, 7.6; N, 7.5.

EXAMPLE 56 (3R,S)-Diphenylmethoxy-1-[2-(2-pyrazinyl)ethyl]piperidine##STR75##

This was prepared as described in Example 54 using 2-vinylpyrazineinstead of 4-vinylpyridine. The title compound was obtained as a palebrown gum (185 mg, 50%).

Analysis %: Found: C, 77.2; H, 7.5; N, 11.2; C₂₄ H₂₇ N₃ O requires: C,77.2; H, 7.3; N, 11.2.

EXAMPLE 57(3R)-[(5H)-Dibenzo[a,d]cyclohepten-5-yloxy]-1-(4-methoxyphenethyl)piperidin##STR76##

A solution of 5-chloro-(5H)-dibenzo[a,d]cycloheptene (0.49 g), [preparedby chlorination of the commercially available 5-hydroxy compound usingthionyl chloride] and (3R)-hydroxy-1-(4-methoxyphenethyl)piperidine (seePreparation 15) (0.47 g) {[α]_(D) ²⁵ -3.0° (c 1.5 in ethanol)} inmethylene chloride was stirred at room temperature for four hours,washed with 2M aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over magnesium sulphate and evaporated. The residue waspurified by chromatography on silica (10 g) using methylene chlorideplus 0-2% methanol as the eluant. Appropriate fractions were combinedand evaporated to give the title compound as a pale orange gum which wascharacterised as a hemihydrate (300 mg, 35%), [α]_(D) ²⁵ +17.4° (c 0.995in methanol).

Analysis %: Found: C, 79.6; H, 7.2; N, 3.1; C₂₉ H₃₁ NO₂ ; 0.5H₂requires: C, 80.1; H, 7.4; N, 3.2.

EXAMPLE 58(3R)-[(5H)-10,11-Dihydrodibenzo[a,d]cyclohepten-5-yl]-1-(4-methoxyphenethyl)piperidine##STR77##

This was prepared as described in Example 57 using5-chloro-(5H)-10,11-dihydrobenzo[a,d]cycloheptene (commerciallyavailable) instead of 5-chloro-(5H)-dibenzo[a,d]cycloheptene. The titlecompound was obtained as a colourless oil which was characterised as ahemihydrate (491 mg, 58%), [α]_(D) ²⁵ +23.8° (c 0.95 in methanol).

Analysis %: Found: C, 79.7; H, 7.6; N, 3.2; C₂₉ H₃₃ NO₂ ; 0.5H₂ Orequires: C, 79.8; H, 7.8; N, 3.2.

EXAMPLE 59(3R)-[(11H)-6,11-Dihydrobenzo[b,e]thiepin-11-yloxy]-1-(4-methoxyphenethyl)piperidine##STR78##

This was prepared as described in Example 57 using11-chloro-(11H)-6,11-dihydrodibenzo[b,e]thiepine (prepared by thechlorination of the commercially available 11-hydroxy compound usingthionyl chloride) instead of 5-chloro-(5H)-dibenzo[a,d]cycloheptene. Thetitle compound was obtained as a colourless oil which was characterisedas a hemihydrate (0.80 g, 90%), [α]_(D) ²⁵ +18.6° (c 0.81 in methanol).

Analysis %: Found: C, 74.0; H, 7.0; N, 2.9; C₂₈ H₃₁ NO₂ S; 0.5H₂ Orequires: C, 74.0; H, 7.1; N, 3.1.

EXAMPLE 60 (3R,S)-Diphenylmethoxy-1-(4-hydroxymethylphenethyl)piperidine##STR79##

A solution of(3R,S)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine (0.43 g)(see Example 17) in ether (5 ml) was added dropwise to a stirredsuspension of lithium aluminium hydride (80 mg) in ether (10 ml) and themixture was stirred at room temperature for four hours, quenched by thesequential addition of water (0.2 ml), 15% aqueous sodium hydroxidesolution (0.2 ml) and water (0.6 ml), and filtered. The filtrate wasevaporated to give the title compound as a colourless solid (270 mg,67%), m.p. 93°-95°.

Analysis %: Found: C, 80.2; H, 7.9; N, 3.3; C₂₇ H₃₁ NO₂ requires: C,80.8; H, 7.7; N, 3.5.

EXAMPLE 61 (3R)-Diphenylmethoxy-1-(4-hydroxymethylphenethyl)piperidine

This was prepared as described in Example 60 using(3R)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine (seeExample 44) instead of(3R,S)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine. Thetitle compound was obtained, after recrystallisation fromtoluene/60°-80° petroleum ether, as a colourless solid (358 mg, 89%),m.p. 94.5°-95°, [α]_(D) ²⁵ +26.3° (c 0.955 in methanol).

Analysis %: Found: C, 80.4; H, 7.8; N, 3.2; C₂₇ H₃₁ NO₂ requires: C,80.8; H, 7.7; N, 3.5.

EXAMPLE 62(3R,S)-Diphenylmethoxy-1-[4-(1-hydroxyethyl)phenethyl]piperidine##STR80##

Sodium borohydride (40 mg) was added to a stirred solution of1-(4-acetylphenethyl)-(3R,S)-diphenylmethoxypiperidine (250 mg) (seeExample 18) in methanol (5 ml) and the mixture was stirred at roomtemperature for fourteen hours, diluted with ethyl acetate, washed twicewith water, dried over magnesium sulphate and evaporated to give thetitle compound as a colourless oil (202 mg, 81%).

Analysis %: Found: C, 80.3; H, 8.1; N, 3.6; C₂₈ H₃₃ NO₂ requires: C,81.0; H, 7.9; N, 3.4.

EXAMPLE 63(3R)-Diphenylmethoxy-1-[4-(1-hydroxyethyl)phenethyl]piperidine

This was prepared as described in Example 62 using1-(4-acetylphenethyl)-(3R)-diphenylmethoxypiperidine (see Example 42)instead of 1-(4-acetylphenethyl)-(3R,S)-diphenylmethoxypiperidine. Thetitle compound was obtained as a yellow oil (131 mg, 33%).

Analysis %: Found: C, 81.2; H, 8.0; N, 3.3; C₂₈ H₃₃ NO₂ requires: C,81.0; H, 8.0; N, 3.4.

EXAMPLE 64 1-(4-Carbamoylphenethyl)-(3R)-diphenylmethoxypiperidine##STR81##

A solution of(3R)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine (0.43 g)(see Example 44) in methanol (10 ml) was treated with 0.880 aqueousammonia (10 ml) and the mixture was heated at 80° for sixteen hours in asteel bomb and then evaporated. The residue was partitioned betweenethyl acetate and water and the organic layer was washed with water,dried over magnesium sulphate and evaporated. The residue was purifiedby chromatography on silica (5 g) using methylene chloride plus 0-5%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless solid which wascharacterised as a hemihydrate (75 mg, 16%), m.p. 144.5°-145.5°, [α]_(D)²⁵ +25.1° (c 0.475 in methanol).

Analysis %: Found: C, 76.9; H, 7.4; N, 6.5; C₂₇ H₃₀ N₂ O₂ ; 0.5H₂ Orequires: C, 76.6; H, 7.4; N, 6.6.

EXAMPLE 65 1-(4-Carbamoylphenethyl)-(3R,S)-diphenylmethoxypiperidine##STR82##

A mixture of(3R,S)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine (0.43 g)(see Example 17) and 0.880 aqueous ammonia solution (5 ml) intetrahydrofuran (5 ml) was heated in a steel bomb at 80° for nineteenhours and then evaporated. The residue was partitioned between ethylacetate and water and the organic layer was washed with water, driedover magnesium sulphate and evaporated. The residue was separated bychromatography on silica (8 g) using methylene chloride:ethyl acetate(4:1) plus 1-20% methanol as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a colourless solidwhich was characterised as a hemihydrate (150 mg, 37%), m.p. 165°-166°.

Analysis %: Found: C, 76.7; H, 7.1; N, 6.6; C₂₇ H₃₀ N₂ O₂ ; 0.5H₂ Orequires: C, 76.6; H, 7.4; N, 6.6.

EXAMPLE 66(3R)-Diphenylmethoxy-1-[4-(N-methylcarbamoyl)phenethyl]piperidine##STR83##

This was obtained as described in Example 64 using 33% ethanolicmethylamine solution instead of 0.880 aqueous ammonia solution. Thetitle compound was obtained as a colourless oil (327 mg, 97%), [α]_(D)²⁵ +24.9° (c 1.005 in methanol).

Analysis %: Found: C, 78.5; H, 7.4; N, 6.4; C₂₈ H₃₂ N₂ O₂ requires: C,78.5; H, 7.5; N, 6.5.

EXAMPLE 67 1-(3-Carbamoylphenethyl)-(3R,S)-diphenylmethoxypiperidine##STR84##

This was prepared as described in Example 64 but using(3R,S)-diphenylmethoxy-1-(3-methoxycarbonylphenethyl)piperidine (seeExample 87) instead of(3R)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine. The titlecompound was obtaianed as a colourless oil (27 mg, 23%).

Analysis %: Found: C, 78.4; H, 7.3; N, 6.5; C₂₇ H₃₀ N₂ O₂ requires: C,78.2; H, 7.3; N, 6.8.

EXAMPLE 68 1-(3-Carbamoylphenethyl)-(3R)-diphenylmethoxypiperidine##STR85##

This was prepared as described in Example 64 using(3R)-diphenylmethoxy-1-(3-methoxycarbonylphenethyl)piperidine (seeExample 88) instead of(3R)-diphenylmethoxy-1-(4-methoxycarbonylphenethyl)piperidine. The titlecompound was obtained as a colourless oil, (0.12 g, 24%).

Analysis %: Found: C, 74.4; H, 7.2; N, 5.6; C₂₇ H₃₀ N₂ O₂.H₂ O requires:C, 75.0; H, 7.4; N, 6.5.

EXAMPLE 69(3R,S)-Diphenymethoxy-1-[3-(N-methylcarbamoyl)phenethyl]piperidine##STR86##

This was prepared as described in Example 64 from(3R,S)-diphenylmethoxy-1-(3-methoxycarbonylphenethyl)piperidine (seeExample 87) and 33% methylamine in ethanol solution. The title compoundwas obtained as a colourless oil (64 mg, 38%).

Analysis %: Found: C, 78.0; H, 7.7; N, 6.4; C₂₈ H₃₂ N₂ O₂ requires: C,78.5; H, 7.5; N, 6.5.

EXAMPLE 70 1-(3-Aminophenethyl)-(3R,S)-diphenylmethoxypiperidine##STR87##

A mixture of (3R,S)-diphenylmethoxy-1-(3-nitrophenethyl)piperidine (4.1g) (see Example 12) and stannous chloride dihydrate (10.8 g) in ethanol(50 ml) was heated under reflux for one hour, diluted with ethyl acetateand saturated aqueous sodium hydrogen carbonate, and the layers wereseparated. The organic layer was washed with water, dried over sodiumsulphate and evaporated. The residue was purified by chromatography onsilica (25 g) using methylene chloride plus 0-2% methanol as the eluant.Appropriate fractions were combined and evaporated to give the titlecompound as an oil (3.26 g, 93%).

Analysis 5: Found: C, 80.8; H, 7.8; N, 7.2; C₂₆ H₃₀ N₂ O requires: C,80.8; H, 7.8; N, 7.2.

EXAMPLE 71-74

The following compounds (R,S-forms) were prepared by reduction of theappropriate nitro-substituted starting materials (R,S-forms) (seeExamples 13, 19, 11 and 24 respectively) with stannous chloridedihydrate as described in Example 70.

Example 72 was characterised by ¹ H-n.m.r. (CDCl₃): δ=7.20-7.50 (10H,m); 6.48-6.66 (3H, m); 5.59 (1H, s); 3.55-3.70 (3H, m); 3.12 (2H, d, J=6Hz); 2.51-2.87 (5H, m) and 1.24-2.15 (6H, m).

In example 71, a solution of ether saturated with hydrogen chloride wasadded to a solution of the crude free base in ether. The mixture waskept at room temperature for 16 hours and the supernatant was decantedfrom the precipitated oil. This oil was dried to give the hydrochloridesalt as a colourless foam. ##STR88##

    __________________________________________________________________________                              Analysis %                                                                    (Theoretical in brackets)                           Example                                                                            R          Form Characterised                                                                      C    H  N                                           __________________________________________________________________________    71                                                                                            Hydrochloride, foam                                                                     .sup. 73.6 (73.8                                                                   7.5 7.4                                                                          6.4 6.6)                                    72                                                                                  ##STR89## Free base, oil                                                                          Characterised by .sup.1 H-n.m.r. (vide infra)       73                                                                                  ##STR90## Free base, oil                                                                          .sup. 77.2 (77.8                                                                   7.8 7.7                                                                          6.6 6.7)                                    74                                                                                  ##STR91## Free base, oil                                                                          .sup. 80.5 (80.8                                                                   7.8 7.8                                                                          7.2 7.2)                                    __________________________________________________________________________

EXAMPLE 75(3R,S)-Diphenylmethoxy-1-(4-methanesulphonamidophenethyl)piperidine##STR92##

Methanesulphonyl chloride (0.165 g) was added dropwise to a stirredsolution of 1-(4-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine (0.50g) (see Example 71) in pyridine (5 ml) and the mixture was stirred atroom temperature for sixteen hours and then evaporated. The residue waspartitioned between methylene chloride and saturated aqueous sodiumhydrogen carbonate solution and the organic layer was washed with water,dried over sodium sulphate and evaporated. The residue was purified bychromatography on silica (8 g) using methylene chloride plus 0-1%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless oil (0.32 g, 53%).

Analysis %: Found: C, 69.7; H, 6.9; N, 6.0; C₂₇ H₃₂ N₂ O₃ S requires: C,69.8; H, 6.9; N, 6.0.

EXAMPLE 76(3R,S)-Diphenylmethoxy-1-(3-methanesulphonamidophenethyl)piperidine##STR93##

This was prepared as described in Example 75 using1-(3-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine (see Example 70)instead of 1-(4-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine. Thetitle compound was obtained as a colourless oil (0.21 g, 35%).

Analysis %: Found: C, 69.9; H, 7.1; N, 6.2; C₂₇ H₃₂ N₂ O₃ S requires: C,69.8; H, 6.9; N, 6.0.

EXAMPLE 77(3R,S)-Diphenylmethoxy-1-(4-ethanesulphonamidophenethyl)piperidine##STR94##

This was prepared as described in Example 75 using ethanesulphonylchloride instead of methanesulphonyl chloride. The title compound wasobtained as a pale yellow oil (0.40 g, 67%).

Analysis %: Found: C, 70.0; H, 7.4; N, 5.8; C₂₈ H₃₄ N₂ O₃ S requires: C,70.3; H, 7.2; N, 5.8.

EXAMPLE 78 1-(4-Acetamidophenethyl)-(3R,S)-diphenylmethoxypiperidine##STR95##

Acetic anhydride (154 mg) was added to a mixture of1-(4-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine (0.50 g) (seeExample 71), sodium hydrogen carbonate (1.0 g), ethyl acetate (5 ml) andwater (5 ml) and the mixture was shaken vigorously for twenty secondsand then allowed to stand at room temperature for ten minutes. Thelayers were separated and the organic layer was washed with saturatedbrine, dried over sodium sulphate and evaporated. The residue waspurified by chromatography on silica (8 g) using methylene chloride plus0-5% methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless oil (0.33 g, 60%).

Analysis %: Found: C, 78.8; H, 7.7; N, 6.8; C₂₈ H₃₂ N₂ O₂ requires: C,78.5; H, 7.5; N, 6.5.

EXAMPLE 79 1-(3-Acetamidophenethyl)-(3R,S)-diphenylmethoxypiperidine##STR96##

This was prepared as described in Example 78 using1-(3-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine (see Example 70)instead of 1-(4-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine. Thetitle compound was obtained as a pale yellow oil which was characterisedwith 0.25 molar equivalents of water (0.35 g, 63%).

Analysis %: Found: C, 77.8; H, 7.6; N, 6.6; C₂₈ H₃₂ N₂ O₂ ; 0.25H₂ O: C,77.6; H, 7.6; N, 6.5.

EXAMPLE 80 1-(4-Acetamidomethylphenethyl)-(3R)-diphenylmethoxypiperidine##STR97##

A mixture of acetic anhydride (115 mg) and1-(4-aminomethylphenethyl)-(3R)-diphenylmethoxypiperidine (407 mg) (seeExample 89) in methylene chloride (35 ml) was stirred at roomtemperature for 18 hours, washed with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and evaporated. Theresidue was purified by chromatography on silica (10 g) using methylenechloride plus 0-5% methanol as the eluant. Appropriate fractions werecombined and evaporated to give the compound as a yellow oil which wascharacterised as a hemihydrate (349 mg, 76%), [α]_(D) ²⁵ +20.6° (c 0.925in methanol).

Analysis %: found: C, 76.8; H, 8.0; N, 5.9; C₂₉ H₃₄ N₂ O₂ ; 0.5H₂ Orequires: C, 77.1; H, 7.8; N, 6.2.

EXAMPLE 81(3R,S)-Diphenylmethoxy-1-(4-sulphamoylaminophenethyl)piperidine##STR98##

A solution of 1-(4-aminophenethyl)-(3R,S)-diphenylmethoxypiperidine(0.45 g) (see Example 71) and sulphamide (1.0 g) in dioxan (10 ml) washeated under reflux for one hour and evaporated. The residue waspartitioned between ethyl acetate and water and the organic layer wasdried over sodium sulphate and evaporated. The residue was purified bychromatography on silica (13 g) using methylene chloride plus 0-5%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless glass (0.24 g,44%).

Analysis %: Found: C, 66.7; H, 6.8; N, 8.8; C₂₆ H₃₁ N₃ O₃ S requires: C,67.1; H, 6.7; N, 9.0.

EXAMPLE 82 (3R,S)-Diphenylmethoxy-1-(3-ethoxyphenethyl)piperidine##STR99##

Sodium hydride (64 mg; 50% suspension in oil) was added to a solution of(3R,S)-diphenylmethoxy-1-(3-hydroxyphenethyl)piperidine (0.46 g) (seeExample 15) in dimethylformamide (10 ml) and the mixture was stirred atroom temperature for 30 minutes, treated with iodoethane (0.19 g) andthen stirred at room temperature for three hours. The mixture waspartitioned between ethyl acetate and water and the organic layer waswashed with water, dried over sodium sulphate and evaporated. Theresidue was purified by chromatography on silica (9 g) using methylenechloride plus 0-1% methanol as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a pale yellow oil(0.38 g, 77%).

Analysis %: Found: C, 80.9; H, 8.1; N, 3.3; C₂₈ H₃₃ NO₂ requires: C,80.9; H, 8.0; N, 3.4.

EXAMPLE 83(3R)-Diphenylmethoxy-1-[4-(N-methylcarbamoyloxy)phenethyl]piperidine##STR100##

Methyl isocyanate (1.0 ml) was added to a solution of(3R)-diphenylmethoxy-1-(4-hydroxyphenethyl)piperidine (0.50 g) (seeExample 35) in methylene chloride (25 ml) and the mixture was stirred atroom temperature for sixty five hours and then evaporated. The residuewas purified by chromatography on silica (4 g) using methylene chlorideplus 0-2% methanol as the eluant. Appropriate fractions were combinedand evaporated to give the title compound as a colourless oil, which wascharacterised as a hemihydrate (401 mg, 70%).

Analysis %: Found: C, 74.0; H, 7.7; N, 6.5; C₂₈ H₃₂ N₂ O₃ ; 0.5H₂ Orequires: C, 74.1; H, 7.3; N, 6.2.

EXAMPLE 841-[2-(5-Carbamoyl-2-thienyl)ethyl]-(3R,S)-diphenylmethoxypiperidine##STR101##

A mixture of1-[2-(5-carboxy-2-thienyl)ethyl]-(3R,S)-diphenylmethoxypiperidine (126mg) (see Preparation 17), and 1,1'-carbonyldiimidazole ("CDI") (49 mg)in tetrahydrofuran (20 ml) was stirred at room temperature for fourhours and then treated with a saturated solution of ammonia intetrahydrofuran (10 ml). The mixture was stirred at room temperature fortwenty two hours and evaporated. The residue was partitioned betweenethyl acetate and water and the organic layer was washed with water,dried over magnesium sulphate and evaporated. The residue was purifiedby chromatography on silica (7 g) using methylene chloride plus 0-20%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless gum (50 mg, 40%).

Analysis %: Found: C, 71.6; H, 6.7; N, 7.0; C₂₅ H₂₈ N₂ O₂ S requires: C,71.4; H, 6.7; N, 6.7.

EXAMPLE 85(3R)-Diphenylmethoxy-1-(4-methylaminomethylphenethyl)piperidine##STR102##

A solution of thionyl chloride (0.2 ml) and(3R)-diphenylmethoxy-1-(4-hydroxymethylphenethyl)piperidine (300 mg)(see Example 61) in methylene chloride (25 ml) was heated under refluxfor 2 hours and evaporated. The residue was azeotroped three times withn-hexane, treated with 33% methylamine in ethanol (25 ml), stirred atroom temperature for sixteen hours and evaporated. The residue waspartitioned between methylene chloride and 10% aqueous sodium carbonatesolution and the organic layer washed with 10% aqueous sodium carbonatesolution and saturated brine, dried over magnesium sulphate andevaporated. The residue was purified by chromatography on silica (10 g)using methylene chloride plus 0-10% methanol as the eluant. Appropriatefractions were combined and evaporated to give the title compound as ayellow oil (55 mg, 18%), [α]_(D) ²⁵ +20.0° (c 0.52 in methanol).

Analysis %: Found: C, 80.8; H, 8.3; N, 7.0; C₂₈ H₃₄ N₂ O requires: C,81.1; H, 8.3; N, 6.8.

EXAMPLE 86(3R)-Diphenylmethoxy-1-(2-hydroxyprop-2-ylphenethyl)piperidine##STR103##

A 1.4M solution of methyllithium in hexane (0.90 ml) was added dropwiseover five minutes to a stirred, ice-cooled solution of1-(4-acetylphenethyl)-(3R)-diphenylmethoxypiperidine (0.50 g) (seeExample 42) in ether (5 ml) and the mixture was stirred at roomtemperature for four hours, quenched with water and diluted with ether.The layers were separated and the organic layer was dried over magnesiumsulphate and evaporated. The residue was purified by chromatography onsilica (10 g) using methylene chloride plus 0-4% methanol as the eluant.Appropriate fractions were combined and evaporated to give, afterrecrystallisation from n-hexane, the title compound as a colourlesssolid, which was characterised as a hemihydrate (21 mg, 4%), m.p.83°-85°.

Analysis %: Found: C, 79.6; H, 8.3; N, 3.3; C₂₉ H₃₅ NO₂ ; 0.5H₂ Orequires: C, 79.4; H, 8.3; N, 3.2.

EXAMPLE 87(3R,S)-Diphenylmethoxy-1-(3-methoxycarbonylphenethyl)piperidine##STR104##

Carbon monoxide was bubbled through a stirred solution of(3R,S)-diphenylmethoxy-1-(3-iodophenethyl)piperidine (1.00 g) (seeExample 23) in methanol (35 ml) to which was then added potassiumcarbonate (0.70 g) and bis(triphenylphosphine)palladium (II) chloride(30 mg). The mixture was stirred at room temperature for three hourswith the continuous passage of carbon monoxide, filtered and evaporated.The residue was partitioned between ethyl acetate and saturated aqueoussodium hydrogen carbonate solution and the organic layer was dried overmagnesium sulphate and evaporated. The residue was purified bychromatography on silica (15 g) using methylene chloride plus 0-2%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a pale yellow oil (0.31 g, 36%)which was characterised by ¹ H-n.m.r.; (CDCl₃); δ=7.91 (2H, s);7.20-7.46 (12H, m); 5.59 (1H, s); 3.97 (3H, s); 3.52-3.63 (1H, m); 3.14(1H, dd, J=6 and 2 Hz); 2.54-2.90 (5H, m) and 1.28-2.20 (6H, m).

EXAMPLE 88 (3R)-Diphenylmethoxy-1-(3-methoxycarbonylphenethyl)piperidine##STR105##

This was prepared as described in Example 87 using(3R)-diphenylmethoxy-1,3-iodophenethyl)piperidine (see Example 52)instead of (3R,S)-diphenylmethoxy-1-(3-iodophenethyl)piperidine. Thetitle compound was obtained as a colourless oil, (0.52 g, 60%), whichwas characterised by ¹ H-n.m.r.

¹ H-n.m.r. (CDCl₃) δ=7.91 (2H, s); 7.20-7.55 (12H, m); 5.60 (1H, s);3.97 (3H, s); 3.52-3.64 (1H, m); 3.13 (1H, dd, J=7 and 2 Hz); and1.25-2.90 (11H, m) ppm.

EXAMPLE 89 1-(4-Aminomethylphenethyl)-(3R)-diphenylmethoxypiperidine##STR106##

A solution of 1-(4-cyanophenethyl)-(3R)-diphenylmethoxypiperidine (3.18g) (see Example 43) and concentrated hydrochloric acid (3.0 ml) inethanol (155 ml) was stirred under 45 p.s.i. (310.3 kPa) of hydrogen inthe presence of 10% palladium on charcoal (0.40 g) for 44 hours,filtered and evaporated. The residue was partitioned between methylenechloride and saturated aqueous sodium hydrogen carbonate solution andthe organic layer was washed with water, dried over magnesium sulphateand evaporated. The residue was purified by chromatography on silica (50g) using methylene chloride plus 0-15% methanol as the eluant.Appropriate fractions were combined and evaporated to give the titlecompound as a colourless oil (2.14 g, 60%).

Analysis 5%: Found: C, 79.5; H, 8.1; N, 6.5; C₂₇ H₃₂ N₂ O requires: C,79.2; H, 8.1; N, 6.8.

EXAMPLE 90(3R)-Diphenylmethoxy-1-[4-(3-methylureidomethyl)phenethyl]piperidine##STR107##

Methyl isocyanate (63 mg) was added to a solution of1-(4-aminomethylphenethyl)-(3R)-diphenylmethoxypiperidine (400 mg) (seeExample 89) in methylene chloride (30 ml) and the mixture was stirred atroom temperature for 19 hours and evaporated. The residue was purifiedby chromatography on silica (10 g) using methylene chloride plus 0-10%methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless oil (320 mg, 70%),[α]_(D) ²⁵ +21.1° (c 0.835 in methanol).

Analysis %: Found: C, 75.8; H, 7.8; N, 9.4; C₂₉ H₃₅ N₃ O₂ requires: C,76.1; H, 7.7; N, 9.2.

EXAMPLE 91(3R,S)-Diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidiniumfumarate

A solution of fumaric acid (0.87 g) in warm ethanol (15 ml) was added toa solution of(3R,S)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine (3.11g) (see Example 1) and the mixture was stirred at room temperature for64 hours. The resulting solid was collected, washed with ether and driedto give the title compound as a colourless solid (3.12 g, 78%), m.p.171°-173°.

Analysis %: Found: C, 70.4; H, 6.4; N, 2.6; C₂₇ H₂₉ NO₃.C₄ H₄ O₄ : C,70.1; H, 6.2; N, 2.6.

EXAMPLE 92(3R)-Diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidiniumfumarate

The title compound was prepared as described in Example 91 using(3R)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine (seeExample 32) instead of(3R,S)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine. Thetitle compound was obtained as a colourless solid (0.53 g, 75%), m.p.167°-169°.

Analysis %: Found: C, 70.0; H, 6.3; N, 2.5; C₂₇ H₂₉ NO₃.C₄ H₄ O₄requires: C, 70.1; H, 6.2; N, 2.6.

EXAMPLE 93 (3R,S)-Diphenylmethoxy-1-(3-methoxyphenethyl)piperidiniumfumarate

The title compound was prepared as described in Example 91 using(3R,S)-diphenylmethoxy-1-(3-methoxyphenethyl)piperidine (see Example 8)instead of(3R,S)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine. Thetitle compound was obtained as a colourless solid (1.80 g, 50%), m.p.148°-150°.

Analysis %: Found: C, 71.6; H, 6.7; N, 2.7; C₂₇ H₃₁ NO₂.C₄ H₄ O₄requires: C, 71.9; H, 6.8; N, 2.7.

EXAMPLE 941-[2-(Benzodioxan-6-yl)ethyl]-(3R,S)-diphenylmethoxypiperidiniumfumarate

The title compound was prepared as described in Example 91 using1-[2-(benzodioxan-6-yl)ethyl]-(3R,S)-diphenylmethoxypiperidine (seeExample 2) instead of(3R,S)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine. Thetitle compound was obtained as a colourless solid (2.53 g, 60%), m.p.213°-214°.

Analysis %: Found: C, 70.3; H, 6.5; N, 2.6; C₂₈ H₃₁ NO₃.C₄ H₄ O₄requires: C, 70.4; H, 6.5; N, 2.6.

EXAMPLE 95 (3R,S)-Diphenylmethoxy-1-(2-hydroxyphenethyl)piperidine##STR108##

Sodium hydride (0.16 g; 60% dispersion in oil) was added to a solutionof butanethiol (0.31 g) in dimethylformamide (15 ml) and the mixture wasstirred at room temperature for 2 hours, treated with a solution of(3R,S)-diphenylmethoxy-1-(2-methoxyphenethyl)piperidine (0.50 g) (seeExample 25) in dimethylformamide (5 ml), and heated under reflux for 3.5hours. The mixture was then partitioned between water and ethyl acetateand the organic layer was washed with water, dried over sodium sulphateand evaporated. The residue was purified by chromatography on silica (5g) using methylene chloride plus 0-2% methanol as the eluant.Appropriate fractions were combined and evaporated to give the titlecompound as a colourless oil (0.21 g).

Analysis %: Found: C, 80.4; H, 7.6; N, 3.3; C₂₆ H₂₉ NO₂ requires: C,80.6; H, 7.5; N, 3.6.

The following Preparations illustrate the preparation of the novelstarting materials used in the previous Examples. All temperatures arein °C.:

PREPARATION 1 (3R,S)-Diphenylmethoxypiperidine Method A ##STR109##

A solution of (3R,S)-hydroxypiperidine (50.5 g), benzhydrol (92.0 g) andpara-toluenesulphonic acid monohydrate ("PTSA") (114.0 g) in toluene(600 ml) was heated under reflux for four hours using a Dean-Starkapparatus to remove the water formed. The mixture was then partitionedbetween 2M aqueous sodium hydroxide solution and ethyl acetate and theorganic layer was washed with water and evaporated. The residue waspartitioned between ether and 10% aqueous citric acid and the acidiclayer was washed with ether, basified with excess solid sodium carbonateand extracted into ether. The organic layer was washed with water, driedover magnesium sulphate and evaporated to give the title compound as acolourless oil (89.2 g, 67%) which was characterised by its ¹ H-n.m.r.spectrum; (CDCl₃): δ=7.22-7.45 (10H, m); 5.59 (1H, s); 3.38-3.48 (1H,m); 3.07 (1H, dd, J=6 and 2 Hz); 2.40-2.88 (3H, m) and 1.30-2.05 (5H,m).

Method B ##STR110##

Trifluoroacetic acid ("TFA") (20 ml) was added cautiously to a stirredsolution of (3R,S)-hydroxypiperidine (5.05 g) in methylene chloride (20ml) and the mixture was treated portionwise with benzhydrol (9.20 g),stirred at room temperature for two hours and evaporated. The residuewas dissolved in dioxan (50 ml), treated with 2M aqueous sodiumhydroxide solution (50 ml), stirred at room temperature for two hoursand partitioned between ether and water. The organic layer was washedwith water, extracted into 2M hydrochloric acid, washed with ether,basified with excess solid sodium carbonate and extracted into ether.The organic layer was washed with water, dried over magnesium sulphateand evaporated to give the title compound as a colourless oil (5.30 g,40%) whose spectral data was identical with that of the product obtainedby Method A.

PREPARATION 2 (3R,S)-Di(4-fluorophenyl)methoxypiperidine ##STR111##

The title compound was prepared as described in Preparation 1, Method Ausing di(4-fluorophenyl)methanol (commercially available) instead ofbenzhydrol. The title compound was obtained as a colourless oil (4.01 g,66%) which was characterised by its ¹ H-n.m.r. spectrum; (CDCl₃): δ=7.31(4H, dt, J=8 and 10 Hz); 7.02 (4H, t, J=8 Hz); 5.50 (1H, s); 3.34-3.42(1H, m); 3.08 (1H, dd, J=6 and 2 Hz); 2.60-2.89 (3H, m) and 1.32-2.00(5H, m).

PREPARATION 3 (3R)-Di(4-fluorophenyl)methoxypiperidine ##STR112##

A mixture of di(4-fluorophenyl)methanol (2.20 g),(3R)-hydroxypiperidinium (1S)-camphor-10-sulphonate (see Preparation 7)(3.30 g) and benzenesulphonic acid (1.58 g) in toluene (60 ml) washeated under reflux in a Dean-Stark apparatus for 3 hours, washed with10% aqueous sodium carbonate solution and evaporated. The residue wasdissolved in ether and extracted with 10% aqueous citric acid solution.The acidic extract was washed with ether, basified with solid sodiumcarbonate and extracted with ether. The organic extract was washed withwater, dried over MgSO₄ and evaporated to give the title compound as acolourless oil, (2.40 g, 79%).

Analysis %: Found: C, 71.7; H, 6.3; N, 4.7; C₁₈ H₁₉ F₂ NO requires: C,71.3; H, 6.3; N, 4.6.

PREPARATION 4 (3R)-[(R,S)-1-(2-Methylphenyl)-1-phenylmethoxy]piperidine##STR113##

This was prepared as described in Preparation 3 using1-(2-methylphenyl)-1-phenylmethanol and para-toluenesulphonic acidinstead of di(4-fluorophenyl)methanol and benzenesulphonic acid. Thetitle compound was obtained as a yellow oil, (5.76 g, 51%), which wasused directly in Example 29 without further purification.

PREPARATION 5(3R)-[(R,S)-1-(2-tert-Butylphenyl)-1-phenylmethoxy]piperidine ##STR114##

This was prepared as described in Preparation 3 using1-(2-tert-butylphenyl)-1-phenylmethanol (see J. Med. Chem., 2, 57(1960)) and para-toluenesulphonic acid instead ofdi(4-fluorophenyl)methanol and benzenesulphonic acid. The title compoundwas obtained as a colourless oil, (847 mg, 72%), which was used directlyin Example 30 without further purification.

PREPARATION 6(3R,S)-[(11H)-6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy]piperidine##STR115##

This was prepared as described in Preparation 1, Method A using(11H)-6,11-dihydrodibenzo[b,e]thiepin-11-ol (commercially available)instead of diphenylmethanol. The title compound was obtained as a paleorange oil (1.00 g, 12%) which was used directly in Example 31 withoutfurther purification or characterisation.

PREPARATION 7 (3R)-Diphenylmethoxypiperidine

This was prepared as described in Preparation 1, Method A using(3R)-hydroxypiperidinium (1S)-camphor-10-sulphonate [prepared by themethod of B. Ringdahl, U. F. W. Ohnsorge and J. C. Craig, [J. Chem. Soc.Perkin II, (1981), 697] [α]_(D) ²⁵ +23.1° (c 1.5 in 50% aqueousethanol)] instead of (3R,S)-hydroxypiperidine. The title compound wasobtained as a colourless oil (2.7 g, 50%), [α]_(D) ²⁵ -3.3° (c 1.5 inethanol).

Analysis %: Found: C, 80.2; H, 7.9; N, 5.1; C₁₈ H₂₁ NO requires: C,80.9; H, 7.9; N, 5.2.

PREPARATION 8(3R,S)-Diphenylmethoxy-1-(3,4-methylenedioxyphenylacetyl)piperidine##STR116##

1-Methylmorpholine (1.50 g) was added to a mixture of(3R,S)-diphenylmethoxypiperidine (0.80 g) (see Preparation 1),3,4-methylenedioxyphenylacetic acid (0.54 g), 1-hydroxybenzotriazole(0.51 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.20 g) in methylene chloride (50 ml) and the solution was stirred atroom temperature for forty hours, washed successively with 2Mhydrochloric acid, water, 10% aqueous sodium carbonate solution andwater, dried over magnesium sulphate and evaporated to give the titlecompound as a colourless oil (1.19 g, 92%), which was characterised byits ¹ H-n.m.r. spectrum (CDCl₃): δ=7.2-7.5 (10H, m); 6.60-6.83 (3H, m);5.98 (2H, s); 5.38 (s) and 5.64 (s) (1H); 3.20-3.95 (7H, m) and1.25-2.00 (4H, m).

PREPARATIONS 9-14

The following compounds (R,S-forms) were prepared by the methoddescribed in Preparation 8 by coupling the appropriate arylacetic acidwith (3R,S)-diphenylmethoxypiperidine (see Preparation 1). Thearylacetic acids are in general known compounds. The starting materialfor Preparation 14 is described in Preparation 18.

The products from Preparations 12 and 13 were characterised by their ¹H-n.m.r. spectra; Preparation 12 (CDCl₃): δ=7.2-7.6 (14H, m); 5.42 (s)and 5.63 (s) (1H); 3.30-3.92 (7H, m) and 1.25-2.00 (4H, m): Preparation13 (CDCl₃): δ=7.22-7.50 (10H, m); 6.61-6.88 (3H, m); 5.36 (s) and 5.64(s) (1H); 4.25 (4H, s); 3.16-4.02 (7H, m) and 1.23-2.00 (4H, m).##STR117##

    ______________________________________                                                                Analysis %                                            Prepara-                (Theoretical in brackets)                             tion   R                C        H    N                                       ______________________________________                                         9                                                                                                    .sup. 77.2 (77.4                                                                       6.5 6.5                                                                            3.5 3.5)                                10                                                                                    ##STR118##      .sup. 78.3 (78.7                                                                       6.9 6.8                                                                            4.0 3.3)                                11                                                                                    ##STR119##      .sup. 74.1 (74.1                                                                       6.0 6.0                                                                            3.2 3.3)                                12                                                                                    ##STR120##      Characterised by .sup.1 H-n.m.r. (vide infra)         13                                                                                    ##STR121##      Characterised by .sup.1 H-n.m.r (vide infra)          14                                                                                    ##STR122##      .sup. 75.5 (76.1                                                                       6.9 6.8                                                                            3.0 3.0)                                ______________________________________                                    

PREPARATION 15 (3R)-Hydroxy-1-(4-methoxyphenethyl)piperidine

A mixture of (3R)-hydroxypiperidinium camphor-10-sulphonate (8.30 g)[prepared by the method of B. Ringdahl, U. F. W. Ohnsorge and J. C.Craig, J. Chem. Soc. Perkin II, (1981), 697] [α]_(D) ²⁵ +23.1° (c 1.5 in50% aqueous ethanol)], 4-methoxyphenethyl bromide (5.4 g), sodiumcarbonate (5.30 g) and sodium iodide (250 mg) in acetonitrile (125 ml)was heated under reflux for 84 hours and evaporated. The residue waspartitioned between methylene chloride and water and the organic layerwas washed with saturated brine, dried over magnesium sulphate andevaporated. The residue was purified by chromatography on silica (60 g)using methylene chloride plus 0-3% methanol as the eluant. Appropriatefractions were combined and evaporated to give the title compound as acolourless oil (3.80 g, 65%), [α]_(D) ²⁵ +1.6° (c 1.0 in methanol),which was characterised by its ¹ H-n.m.r. spectrum: (CDCl₃): δ=7.15 (2H,d, J=8 Hz); 6.83 (2H, d, J=8 Hz); 3.80-3.88 (1H, m); 3.79 (3H, s);2.32-2.80 (9H, m) and 1.48-1.92 (4H, m).

PREPARATION 16 (3R,S)-Hydroxy-1-(3-methoxyphenethyl)piperidine

This was prepared as described in Preparation 15 from(3R,S)-hydroxypiperidine and 3-methoxyphenethyl bromide. The titlecompound was obtained as a pale yellow oil (1.63 g, 72%) which wascharacterised by its ¹ H-n.m.r. spectrum; (CDCl₃): δ=7.21 (1H, dd, J=8and 7 Hz); 6.72-6.83 (3H, m); 3.78-3.88 (1H, m); 3.81 (3H, s); 2.30-2.84(9H, m) and 1.47-1.90 (4H, m).

PREPARATION 171-[2-(5-Carboxy-2-thienyl)ethyl]-(3R,S)-diphenylmethoxypiperidine##STR123##

A 2.6M solution of n-butyllithium in hexane (1.28 ml) was added dropwiseover ten minutes to a stirred solution of(3R,S)-diphenylmethoxy-1-[2-(2-thienyl)ethyl]piperidine (378 mg) (seeExample 21) in ether (25 ml) at -20° and the mixture was stirred at -20°for one hour and poured onto a mixture of solid carbon dioxide andether. The mixture was diluted with water and the layers were separated.The aqueous layer was acidified with glacial acetic acid to pH 7 andextracted into ethyl acetate. The ethyl acetate extract was washed withwater, dried over sodium sulphate and evaporated. The residue waspurified by chromatography on silica (7 g) using methylene chloride plus0-20% methanol as the eluant. Appropriate fractions were combined andevaporated to give the title compound as a colourless gum (70 mg, 17%).

Analysis %: Found: C, 70.9; H, 6.3; N, 3.3; C₂₅ H₂₇ NO₃ S requires: C,71.2; H, 6.5; N, 3.3.

PREPARATION 18 (Benzodioxepan-7-yl)acetic acid ##STR124##

A mixture of 3,4-dihydroxyphenylacetic acid (5.0 g), 1,3-dibromopropane(7.2 g) and potassium hydroxide (7.3 g) in water (25 ml) was heatedunder reflux for 17 hours, acidified to pH 1 with 2M hydrochloric acidand extracted several times into methylene chloride. The combinedorganic extracts were dried over magnesium sulphate and evaporated. Theresidue was purified by chromatography on silica (75 g) using methylenechloride plus 0-2% acetic acid as the eluant. Appropriate fractions werecombined and evaporated and the residue was taken up in methylenechloride and extracted into 5% aqueous sodium carbonate solution. Thebasic extract was washed with methylene chloride, acidified to pH 1 with5M hydrochloric acid and extracted into methylene chloride. The organicextract was dried over magnesium sulphate and evaporated to give thetitle compound as a colourless solid (1.4 g, 23%), m.p. 99°-101°.

Analysis %: Found: C, 63.4; H, 5.9; N, 0.0; C₁₁ H₁₂ O₄ requires: C,63.4; H, 5.8; N, 0.0.

PREPARATION 19 3,4-Methylenedioxyphenethyl alcohol ##STR125##

3,4-Methylenedioxyphenylacetic acid (18.0 g) was added portionwise over30 minutes to a stirred, ice-cooled suspension of lithium aluminiumhydride (4.0 g) in ether (400 ml) and the mixture was stirred attemperature for two hours, quenched by the cautious addition ofsaturated aqueous ammonium chloride solution and filtered. The filtratewas washed with 10% aqueous sodium carbonate solution, dried overmagnesium sulphate and evaporated to give the title compound as a paleyellow oil (15.01 g, 90%), which was characterised by its ¹ H-n.m.r.spectrum.

¹ H-n.m.r. (CDCl₃) δ=6.69-6.83 (3H, m); 5.98 (2H, s); 3.82 (2H, dt, J=7and 6 Hz); 2.81 (2H, t, J=7 Hz) and 1.44 (1H, t, J=6 Hz, exchangeablewith D₂ O).

PREPARATION 20 3,4-Methylenedioxyphenethyl bromide ##STR126##

A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50ml) was added dropwise over 30 minutes to a stirred solution of3,4-methylenedioxyphenethyl alcohol (15.0 g) (see Preparation 19) incarbon tetrachloride (200 ml) and the mixture was heated under refluxfor 3 hours, washed sequentially with water (twice), 5M aqueous sodiumhydroxide solution and water, dried over magnesium sulphate andevaporated. The residue was purified by chromatography on silica (100 g)using carbon tetrachloride as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a pale yellow oil(8.3 g, 40%), which was characterised by its ¹ H-n.m.r. spectrum.

¹ H-n.m.r. (CDCl₃) δ=6.80 (1H, d, J=8 Hz), 6.75 (1H, s); 6.71 (1H, d,J=8 Hz); 6.00 (2H, s); 3.56 (2H, t, J=7 Hz) and 3.13 (2H, t, J=7 Hz).

PREPARATION 21 3-Hydroxy-4-methoxyphenethyl chloride ##STR127##

A mixture of 3-hydroxy-4-methoxyphenethyl alcohol (2.25 g) and thionylchloride (5 ml) in methylene chloride (120 ml) was heated under refluxfor 16 hours and evaporated. The residue was azeotroped twice withhexane and purified by chromatography on silica (30 g) using methylenechloride plus 0-6% methanol as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a colourless solid(0.82 g, 33%), m.p. 53°-54°, which was characterised by its ¹ H-n.m.r.spectrum.

¹ H-n.m.r. (CDCl₃) δ=6.86 (1H, d, J=8 Hz); 6.82 (1H, d, J=2 Hz); 6.73(1H, dd, J=8 and 2 Hz); 5.61 (1H, s, exchangeable with D₂ O); 3.92 (3H,s); 3.70 (2H, t, J=7 Hz) and 3.01 (2H, t, J=7 Hz).

PREPARATION 22 6-(2-Hydroxyethyl)benzodioxan ##STR128##

This was prepared as described in Preparation 19 using(benzodioxan-6-yl)acetic acid instead of 3,4-methylenedioxyphenylaceticacid. The title compound was obtained as a colourless oil (19.8 g, 92%),which was characterised by its ¹ H-n.m.r. spectrum.

¹ H-n.m.r. (CDCl₃) δ=6.84 (1H, d, J=8 Hz); 6.77 (1H, d, J=2 Hz); 6.73(1H, dd, J=8 and 2 Hz); 4.28 (4H, s); 3.59 (2H, t, J=7 Hz) and 3.08 (2H,t, J=7 Hz).

PREPARATION 23 6-(2-Bromoethyl)benzodioxan ##STR129##

This was prepared as described in Preparation 20 using6-(2-hydroxyethyl)benzodioxan (see Preparation 22) instead of3,4-methylenedioxyphenethyl alcohol. The title compound was obtained asa pale yellow oil (21.4 g, 80%), which was characterised by its ¹H-n.m.r. spectrum.

¹ H-n.m.r. (CDCl₃) δ=6.83 (1H, d, J=8 Hz); 6.77 (1H, d, J=2 Hz); 6.72(1H, dd, J=8 and 2 Hz); 4.28 (4H, s); 3.59 (2H, t, J=7 Hz) and 3.10 (2H,t, J=7 Hz).

PREPARATION 24 4-Hydroxy-3-nitrophenethyl chloride ##STR130##

A solution of concentrated nitric acid (1.8 ml) in acetic acid (4 ml)was added to a stirred solution of 4-hydroxyphenethyl chloride (4.5 g)in acetic acid (25 ml), keeping the temperature below 15°. The mixturewas then stirred at 10° for 3.5 hours, poured into water, and extractedinto ethyl acetate. The organic extract was washed with 5% aqueoussodium carbonate solution, dried over magnesium sulphate and evaporated.The residue was purified by chromatography on silica (50 g) using hexaneplus 0-10% ethyl acetate as the eluant. Appropriate fractions werecombined and evaporated to give the title compound as a colourless solid(3.2 g, 55%), m.p. 53°-55°.

Analysis %: Found: C, 48.0; H, 3.7; N, 6.9; C₈ H₈ ClNO₃ requires: C,47.6; H, 4.0; N, 6.9.

PREPARATION 25 4-Methoxy-3-nitrophenethyl chloride ##STR131##

This was prepared as described in Preparation 24 using4-methoxyphenethyl chloride instead of 4-hydroxyphenethyl chloride. Thetitle compound was obtained as a pale yellow oil (1.9 g, 18%).

Analysis %: Found: C, 50.4; H, 4.6; N, 6.5; C₉ H₁₀ ClNO₃ requires: C,50.1; H, 4.7; N, 6.5.

PREPARATION 26 3-Iodophenethyl alcohol ##STR132##

This was prepared as described in Preparation 19 using3-iodophenylacetic acid (commercially available) instead of3,4-methylenedioxyphenylacetic acid. The title compound was obtained asa colourless oil (2.2 g, 58%), which was characterised by its ¹ H-n.m.r.spectrum.

¹ H-n.m.r. (CDCl₃) δ=7.58-7.70 (2H, m); 7.23 (1H, d, J=8 Hz); 7.04 (1H,d, J=8 Hz); 3.91 (2H, t, J=7 Hz); 2.84 (2H, t, J=7 Hz) and 1.43 (1H,broad s, exchangeable with D₂ O).

PREPARATION 27 3-Iodophenethyl bromide ##STR133##

A mixture of 3-iodophenethyl alcohol (see Preparation 26) (1.2 g) and48% aqueous hydrobromic acid (20 ml) was stirred at room temperature for8 hours, poured into water and extracted into methylene chloride. Theorganic extracts were washed with saturated aqueous sodium hydrogencarbonate solution and water, dried over sodium sulphate and evaporatedto give the title compound as a pale brown oil (1.1 g, 73%), which wascharacterised by its ¹ H-n.m.r. spectrum.

¹ H-n.m.r. (CDCl₃) δ=7.60-7.70 (2H, m); 7.22 (1H, d, J=8 Hz); 7.07 (1H,t, J=8 Hz); 3.58 (2H, t, J=7 Hz) and 3.16 (2H, t, J=7 Hz).

PREPARATION 28N-[4-(2-methylsulphonyloxyethyl)phenyl]methanesulphonamide ##STR134##

Methanesulphonyl chloride (50.4 g) was added dropwise to a stirredsolution of 4-aminophenethyl alcohol (27.44 g) in dry pyridine (300 ml)at 0° C. and the solution was stirred at 0° C. for 30 minutes and thenat room temperature for 2.5 hours. It was then poured into water and thesolid was filtered off, washed with water, dried and crystallised fromethyl acetate to give the title compound (39.0 g, 66%), m.p. 136°-137°C.

Analysis %: Found: C, 40.6; H, 5.2; N, 4.9; C₁₀ H₁₅ NO₅ S₂ requires: C,40.9; H, 5.1; N, 4.8.

PREPARATION 29 5-(2-Bromoethyl)indane ##STR135##

Phosphorous tribromide (3.5 ml) was added, dropwise, to an ice-cooledsolution of 5-(2-hydroxyethyl)indane (prepared as described inFR-2,139,628) (14.0 g) in carbon tetrachloride (100 ml) and the mixturewas heated under reflux for 2 hours, quenched with ice-water andpartitioned between dichloromethane and 10% aqueous sodium carbonatesolution. The organic layer was washed with water, dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using dichloromethane as eluant.Appropriate fractions were combined and evaporated under reducedpressure to give the title compound as a pale yellow oil, (10.5 g, 54%).

¹ H-n.m.r. (300 MHz. CDCl₃) δ=7.20 (dd, 1H, J=8 and 1.5 Hz); 7.10 (d,1H, J=1.5 Hz); 6.99 (d, 1H, J=8 Hz); 3.58 (t, 2H, J=7 Hz); 3.17 (t, 2H,J=7 Hz); 2.80-3.02 (m, 4H); and 2.02-2.18 (m, 2H) ppm.

PREPARATION 30 5-(2-Hydroxyethyl)-2,3-dihydrobenzofuran ##STR136##

A solution of (2,3-dihydrobenzofuran-5-yl)acetic acid (4.9 g--seeEP-A-132130) in anhydrous tetrahydrofuran (50 ml) was added dropwiseover 10 minutes to a stirred suspension of lithium aluminium hydride(1.57 g) in anhydrous tetrahydrofuran (50 ml) at 0° C. The mixture wasallowed to warm to room temperature and stirred for 1 hour. Water (1.5ml) was cautiously added dropwise followed by 10% aqueous sodiumhydroxide (1.5 ml) and, finally, water (4.5 ml). The mixture wasfiltered and the inorganic salts washed with ethyl acetate (2×50 ml).The filtrate and washings were combined and concentrated in vacuo togive the title compound as as oil, (3.3 g).

¹ H-n.m.r. (CDCl₃) δ=7.10 (s, 1H); 7.00 (d, 1H); 6.75 (m, 1H); 4.65-4.55(m, 2H); 3.90-3.75 (m, 2H); 3.30-3.15 (m, 2H); 2.90-2.80 (m, 2H);1.85-1.75 (broad s, 1H) ppm.

PREPARATION 31 5-(2-Bromoethyl)-2,3-dihydrobenzofuran ##STR137##

Phosphorus tribromide (0.37 g) was added to a solution of5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (0.612 g--see Preparation 30)in carbon tetrachloride (3 ml) and the mixture was heated under refluxfor 3 hours. On cooling to room temperature, the mixture was partitionedbetween 10% aqueous sodium carbonate (20 ml) and dichloromethane (20ml). The layers were separated and the aqueous layer was extracted withdichloromethane (2×10 ml). The combined dichloromethane extracts weredried (MgSO₄) and concentrated in vacuo to give the title compound as anoil which crystallised on standing, (0.584 g), m.p. 60°-62° C.

¹ H-n.m.r. (CDCl₃) δ=7.10 (s, 1H); 7.00-6.95 (d, 1H); 6.80-6.70 (d, 1H);4.65-4.55 (t, 2H); 3.60-3.50 (t, 2H); 3.25-3.15 (t, 2H); 3.15-3.10 (t,2H) ppm.

We claim:
 1. A compound having the (3R,S)- or (3R)-configuration of theformula: ##STR138## or a pharmaceutically acceptable acid addition saltthereof, wherein R¹ is a group of the formula: ##STR139## where each Y,which may be the same or different, is selected from hydrogen, halogenand C₁ -C₄ alkyl; and X is --(CH₂)₂ --, --CH═CH--, --CH₂ --S--, --CH₂O--, --S-- or --O--; andR is a group of the formula: ##STR140## where R²and R³, taken together, and attached to adjacent carbon atoms, representa group of the formula --O(CH₂)_(m) O-- where m is 1, 2 or 3, --O(CH₂)₂-- or --(CH₂)₃ --.
 2. A compound as claimed in claim 1 wherein R is:##STR141## and R² and R³ are as previously defined in claim
 1. 3. Acompound as claimed in claim 1 whereinR¹ is a group selected from thegroup consisting of diphenylmethyl, di(4-fluorophenyl)methyl,1-(2-methylphenyl)-1-phenyl-methyl,1-(2-tert-butylphenyl)-1-phenyl-methyl,(11H)-6,11-dihydrodibenzo[b,e]thiepin-11-yl,(5H)-dibenzo[a,d]-cyclohepten-5-yl and(5H)-10,11-dihydrodibenzo[a,d]cyclohepten-5-yl.
 4. A compound as claimedin claim 1 wherein R¹ is diphenylmethyl.
 5. A compound as claimed inclaim 1 wherein R² and R³ represent --O(CH₂)_(m) O-- where m is 1,whereby R is 3,4-methylenedioxyphenyl.
 6. A compound as claimed in claim1 wherein R¹ is diphenylmethyl and R is 3,4-methylenedioxyphenyl.
 7. Acompound as claimed in claim 1 which has the (3R,S)-configuration.
 8. Acompound as claimed in claim 1 which has the (3R)-configuration. 9.(3R)-Diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine.
 10. Apharmaceutical composition useful for treating diseases associated withaltered motility or smooth muscle tone or both, said compositioncomprising a pharmaceutically acceptable carrier or diluent and ananticholinergically-effective amount of a compound as claimed inclaim
 1. 11. The composition according to claim 10 wherein the compoundis (3R)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine.
 12. Amethod for treating diseases associated with altered motility or smoothmuscle tone or both in a mammal in need of such treatment, whichcomprises administering to said subject ananti-cholinergically-effective amount of a compound as claimed inclaim
 1. 13. The method as claimed in claim 12 wherein said compound is(3R)-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)piperidine.
 14. Themethod as claimed in claim 12 wherein said mammal in need of treatmentis afflicted with a disease selected from the group consisting ofirritable bowel syndrone, diverticular disease, urinary incontinence,oesophageal achalasia and chronic obstructive airways disease.